HINT1

Summary

HINT1 (histidine triad nucleotide binding protein 1, HGNC:4912) is a protein-coding gene on chromosome 5q23.3, encoding Adenosine 5’-monophosphoramidase HINT1 (P49773). Exhibits adenosine 5’-monophosphoramidase activity, hydrolyzing purine nucleotide phosphoramidates with a single phosphate group such as adenosine 5’monophosphoramidate (AMP-NH2) to yield AMP and NH2.

This gene encodes a protein that hydrolyzes purine nucleotide phosphoramidates substrates, including AMP-morpholidate, AMP-N-alanine methyl ester, AMP-alpha-acetyl lysine methyl ester, and AMP-NH2. The encoded protein interacts with these substrates via a histidine triad motif. This gene is considered a tumor suppressor gene. In addition, mutations in this gene can cause autosomal recessive neuromyotonia and axonal neuropathy. There are several related pseudogenes on chromosome 7. Several transcript variants have been observed.

Source: NCBI Gene 3094 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Charcot-Marie-Tooth disease (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 151 total — 21 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 57
• Druggable target: yes
• MANE Select transcript: NM_005340

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4912
Approved symbol	HINT1
Name	histidine triad nucleotide binding protein 1
Location	5q23.3
Locus type	gene with protein product
Status	Approved
Aliases	PKCI-1
Ensembl gene	ENSG00000169567
Ensembl biotype	protein_coding
OMIM	601314
Entrez	3094

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 7 protein_coding, 7 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000304043, ENST00000504202, ENST00000506207, ENST00000506908, ENST00000508488, ENST00000508495, ENST00000511475, ENST00000513012, ENST00000513345, ENST00000520028, ENST00000675100, ENST00000675135, ENST00000675372, ENST00000675491, ENST00000676117, ENST00000857798, ENST00000940010

RefSeq mRNA: 1 — MANE Select: NM_005340 NM_005340

CCDS: CCDS4147

Canonical transcript exons

ENST00000304043 — 3 exons

Exon	Start	End
ENSE00001130414	131159027	131159611
ENSE00001130420	131165095	131165256
ENSE00003527970	131162572	131162676

Expression profiles

Bgee: expression breadth ubiquitous, 302 present calls, max score 99.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 300.8663 / max 2353.4496, expressed in 1829 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63253	296.1787	1829
63252	4.3293	1530
63254	0.3583	69

Top tissues by expression

302 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.93	gold quality
oocyte	CL:0000023	99.83	gold quality
middle temporal gyrus	UBERON:0002771	99.80	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.74	gold quality
adult organism	UBERON:0007023	99.73	gold quality
pons	UBERON:0000988	99.65	gold quality
epithelium of nasopharynx	UBERON:0001951	99.60	gold quality
nasopharynx	UBERON:0001728	99.58	gold quality
gingival epithelium	UBERON:0001949	99.58	gold quality
renal medulla	UBERON:0000362	99.53	gold quality
seminal vesicle	UBERON:0000998	99.50	gold quality
dorsal root ganglion	UBERON:0000044	99.49	gold quality
colonic mucosa	UBERON:0000317	99.47	gold quality
germinal epithelium of ovary	UBERON:0001304	99.47	gold quality
caput epididymis	UBERON:0004358	99.47	gold quality
gingiva	UBERON:0001828	99.46	gold quality
corpus epididymis	UBERON:0004359	99.46	gold quality
secondary oocyte	CL:0000655	99.45	gold quality
oral cavity	UBERON:0000167	99.45	gold quality
prefrontal cortex	UBERON:0000451	99.45	gold quality
mucosa of transverse colon	UBERON:0004991	99.44	gold quality
superior vestibular nucleus	UBERON:0007227	99.44	gold quality
ileal mucosa	UBERON:0000331	99.43	gold quality
upper leg skin	UBERON:0004262	99.42	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.41	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.40	gold quality
type B pancreatic cell	CL:0000169	99.39	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.38	gold quality
mammalian vulva	UBERON:0000997	99.37	gold quality
substantia nigra pars compacta	UBERON:0001965	99.37	gold quality

Single-cell (SCXA)

Detected in 17 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	1574.46
E-MTAB-9221	yes	49.46
E-MTAB-9067	yes	28.66
E-CURD-46	yes	23.89
E-CURD-112	yes	20.81
E-MTAB-8142	yes	17.41
E-HCAD-1	yes	15.75
E-MTAB-10042	yes	15.65
E-MTAB-7316	yes	10.86
E-CURD-88	yes	4.40
E-GEOD-130148	yes	4.36
E-CURD-98	no	2746.67
E-MTAB-9435	no	1562.07
E-CURD-79	no	1458.24
E-MTAB-8207	no	1304.38

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): JUN, LHX2, MITF, MYC, NFKB, PITX2, USF2

miRNA regulators (miRDB)

14 targeting HINT1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-4744	99.01	69.91	1581
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-4774-3P	98.90	67.82	737
HSA-MIR-4742-5P	98.89	68.41	1542
HSA-MIR-5197-3P	98.71	67.05	1905
HSA-MIR-6830-3P	98.62	68.07	1760
HSA-MIR-4317	98.49	67.09	987
HSA-MIR-595	98.25	67.44	699
HSA-MIR-1912-5P	97.94	67.98	832
HSA-MIR-1243	97.07	65.44	719
HSA-MIR-3654	96.43	66.55	646

Literature-anchored findings (GeneRIF, showing 40)

• Reduction of nucleoside diphosphate kinase B, Rab GDP-dissociation inhibitor beta and histidine triad nucleotide-binding protein in fetal Down syndrome brain. (PMID:11771757)
• Hint is an adenosine 5’-monophosphoramidase. Hint does not bind zinc, hydrolyze diadenosine polyphosphates, not inhibit protein kinase C. In yeast, Hnt1 is a positive regulator of Kin28 (human Cdk7) and enzyme activity is required for this function. (PMID:11805111)
• the Hint1 pro-apoptotic activity is independent of the Hint1 enzymatic activity (PMID:16835243)
• The major function of PKCI-1 is to modulate mu opioid receptor signaling pathway along with RGSZ1, rather than directly mediating the Galphaz RGSZ1 interaction. (PMID:17126529)
• Human Hint1/Eoli HinT chimera does not exhibit a preference for phosphoramidates containing d- or l- tryptophan, while the E coli/human chimera adopts the human enzyme preference for the l configuration. (PMID:17939685)
• Activation of protein kinase G Increases the expression of p21CIP1, p27KIP1, and histidine triad protein 1 through Sp1. (PMID:18593937)
• variants at HINT1 may be associated with schizophrenia and the associations may be sex-specific. (PMID:18799291)
• relationship between Hint1 methylation status and clinical features and other, previously measured biomarkers was also analyzed. p16 hypermethylation was statistically significantly associated with Hint1 methylation status (PMID:19081673)
• decreased expression of the Hint1 gene through epigenetic silencing may play a role in enhancing the growth of a subset of human hepatoma by increasing the expression of genes controlled by the transcription factors beta-catenin, USF2, and NFkappaB. (PMID:19089909)
• HINT1 up-regulates cellular levels of p27(KIP1) by two mechanisms: 1) it inhibits its ubiquitylation by targeting the SCF(SKP2) ubiquitin ligase complex, and 2) it inhibits the phosphorylation of p27(KIP1) by Src via inhibiting Src expression. (PMID:19112177)
• Hint1 exerts its major cellular function as gene transcription regulator, and thus, this function provides its potential role as a tumor suppressor protein. (PMID:20499681)
• Results indicate a genetic association between HINT1 variants and ND, and indicate that nicotine-induced modulation of HINT1 level may be involved in mechanisms of excess smoking. (PMID:20514075)
• Hint1 expression was lower in gastric cancer (GC) tissues. (PMID:21468541)
• HINT1 is differentially expressed in schizophrenia brain. (PMID:21553311)
• This study demonistrated that HINT1 is found to be downregulated in the dorsolateral prefrontal cortex and upregulated in the thalamus. (PMID:21553311)
• evaluation of potential inhibitors of human and Escherichia coli histidine triad nucleotide binding proteins (PMID:22104145)
• The results reveal the structural basis for the remarkable adenylate surveillance activity of Hint1, to potentially control Ap(4)A levels in the cell. (PMID:22329685)
• The tumor suppressor activity of HINT1 gene in melanoma cells by promoting the formation of non-functional complexes with oncogenic transcription factors, like MITF and beta-catenin, known to be involved in melanoma development and progression. (PMID:22647378)
• structure of the human HINT1-adenosine 5’-monophosphate (AMP) complex at 1.38 A resolution obtained from a new monoclinic crystal form is reported (PMID:22869114)
• loss of functional HINT1 protein results in a distinct phenotype of autosomal recessive axonal neuropathy with neuromyotonia. (PMID:22961002)
• hHint1 catalyzes the hydrolysis of phosphoramidate and acyl adenylate with high efficiency. (PMID:23614568)
• Histidine triad nucleotide-binding protein 1, bifunctional aminoacyl-tRNA synthetase, and clusterin precursor protein may serve as potential biomarkers distinguishing type 2 diabetes mellitus patients from healthy controls. (PMID:23769013)
• Data suggest that histidine triad nucleotide binding protein 1 (HINT1) should be added to the list of genes to check for in distal hereditary motor neuropathies (dHMNs). (PMID:24105373)
• BTF3, HINT1, NDRG1 and ODC1 protein over-expression in human prostate cancer tissue (PMID:24386364)
• Study gives suggestive evidence that HINT1 rs3852209 may be related to smoking status in Chinese men. (PMID:24447405)
• HINT1 mutations seem to be one of the most frequent causes of inherited neuropathy and are probably the most frequent cause of HMN in Czech patients. We suggest all HMN/CMT2 patients be tested for the presence of the prevalent mutation, the p.R37P (PMID:25342199)
• The teneurin-1 intracellular domain binds HINT1, thus switching on MITF-dependent transcription of GPNMB. (PMID:25648896)
• Absence of HINT1 mutations in a UK and Spanish cohort of patients with inherited neuropathies (PMID:26194197)
• In hepatocellular carcinoma, HINT1 is a regulator of IkappaBalpha through SCF(beta-TrCP) E3 ligase. (PMID:26520111)
• first structure (at a 2.34A resolution) of a complex of human HINT1 with a non-hydrolyzable analog of an Ap4A dinucleotide (PMID:26905466)
• Underexpression of Hint1 is associated with invasion of hepatocellular carcinoma. (PMID:27623945)
• We provide a comprehensive overview of the structural and functional characteristics of the HINT1 protein that may guide further studies into the molecular aetiology and treatment strategies–{REVIEW} (PMID:28007994)
• Hint1 has been shown to be essential for the metabolic activation of nucleotide antiviral pronucleotides (i.e., proTides). These results provide mechanistic insights underpinning histidine nucleophilic catalysis in general and human Hint1 catalysis, in particular, thus aiding the design of future proTides and the elucidation of the natural function of the Hint family of enzymes. (PMID:28691797)
• Thus, hHint1 appears to be structurally sensitive to irreversible inactivation by copper, which may be of neurotoxicological and pharmacological significance. (PMID:28739258)
• the role of HINT1 neuropsychiatric disorders was summarized [review] (PMID:29125116)
• HINT1 mutations R37P, G93D and W123* destabilize the HINT1 dimer and significantly reduce catalytic activity and HINT1 inhibitor binding activity. The H112N mutant is dimeric and lacks catalytic activity, but has high affinity to AMP and a HINT1 inhibitor. Catalytic activity and dimeric structure of the surface mutants, C84R and G89V are similar to wild-type HINT1. (PMID:29787766)
• Two homozygous missense mutations in HINT1 gene were identified in two cases of axonal neuropathy with neuromyotonia. (PMID:30006059)
• The human HINT1 mutants reported to cause ARAN-NM all exhibited deficiencies in their sumoylase activity, thus suggesting a role for HINT1 isopeptidase activity in the pathogenesis of this human motor disease. (PMID:31088288)
• The c.335C>T (p.R119W) of the HINT1 gene probably underlies neuromyotonia and axonal neuropathy in this pedigree. (PMID:31400136)
• Ap4A binds to the histidine triad nucleotide-binding protein 1 (HINT1), disrupts its interaction with the microphthalmia-associated transcription factor (MITF), and eventually activates the transcription of genes downstream of MITF in response to immunostimulation. (PMID:31604935)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hint1	ENSMUSG00000020267
rattus_norvegicus	Hint1l2	ENSRNOG00000005630
rattus_norvegicus	Hint1l2	ENSRNOG00000069792
rattus_norvegicus	Hint1	ENSRNOG00000086472
caenorhabditis_elegans	hint-1	WBGENE00009002

Paralogs (2): HINT2 (ENSG00000137133), FHIT (ENSG00000189283)

Protein

Protein identifiers

Adenosine 5’-monophosphoramidase HINT1 — P49773 (reviewed: P49773)

Alternative names: Desumoylating isopeptidase HINT1, Histidine triad nucleotide-binding protein 1, Protein kinase C inhibitor 1, Protein kinase C-interacting protein 1

All UniProt accessions (8): A0A384NPU2, A0A6Q8PGQ8, D6RC06, D6RD60, D6RE99, D6REP8, P49773, H0YC49

UniProt curated annotations — full annotation on UniProt →

Function. Exhibits adenosine 5’-monophosphoramidase activity, hydrolyzing purine nucleotide phosphoramidates with a single phosphate group such as adenosine 5’monophosphoramidate (AMP-NH2) to yield AMP and NH2. Hydrolyzes adenosine 5’monophosphomorpholidate (AMP-morpholidate) and guanosine 5’monophosphomorpholidate (GMP-morpholidate). Hydrolyzes lysyl-AMP (AMP-N-epsilon-(N-alpha-acetyl lysine methyl ester)) generated by lysine tRNA ligase, as well as Met-AMP, His-AMP and Asp-AMP, lysyl-GMP (GMP-N-epsilon-(N-alpha-acetyl lysine methyl ester)) and AMP-N-alanine methyl ester. Hydrolyzes 3-indolepropionic acyl-adenylate, tryptamine adenosine phosphoramidate monoester and other fluorogenic purine nucleoside tryptamine phosphoramidates in vitro. Can also convert adenosine 5’-O-phosphorothioate and guanosine 5’-O-phosphorothioate to the corresponding nucleoside 5’-O-phosphates with concomitant release of hydrogen sulfide. In addition, functions as scaffolding protein that modulates transcriptional activation by the LEF1/TCF1-CTNNB1 complex and by the complex formed with MITF and CTNNB1. Modulates p53/TP53 levels and p53/TP53-mediated apoptosis. Modulates proteasomal degradation of target proteins by the SCF (SKP2-CUL1-F-box protein) E3 ubiquitin-protein ligase complex. Also exhibits SUMO-specific isopeptidase activity, deconjugating SUMO1 from RGS17. Deconjugates SUMO1 from RANGAP1.

Subunit / interactions. Homodimer. Interacts with CDK7. Interacts with RUVBL1 and RUVBL2 and is associated with the LEF1/TCF1-CTNNB1 complex and with a KAT5 histone acetyltransferase complex. Identified in a complex with MITF and CTNNB1. Interacts with CDC34 and RBX1, and is part of a SCF (SKP2-CUL1-F-box protein) E3 ubiquitin-protein ligase complex. Interacts with SUMO1, SUMO2 and RGS17. Interacts with the Ten-1 ICD form of TENM1. Interacts with CALM1; interaction increases in the presence of calcium ions.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Widely expressed.

Post-translational modifications. Deubiquitinated by USP40, leading to stabilization.

Disease relevance. Neuromyotonia and axonal neuropathy, autosomal recessive (NMAN) [MIM:137200] An autosomal recessive neurologic disorder characterized by onset in the first or second decade of a peripheral axonal neuropathy predominantly affecting motor more than sensory nerves. The axonal neuropathy is reminiscent of Charcot-Marie-Tooth disease type 2 and distal hereditary motor neuropathy. Individuals with NMAN also have delayed muscle relaxation and action myotonia associated with neuromyotonic discharges on needle EMG resulting from hyperexcitability of the peripheral nerves. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Involved in the activation pathway of bemnifosbuvir (AT-527) and its epimer, AT-752. AT-527 and AT-752 are two guanosine analogs tested in clinical trials against several RNA viruses, which are activated into their common 5’-triphosphate AT-9010 in human cells. Mediates the second activation step by catalyzing transformation of AT-551 into AT-8003.

Similarity. Belongs to the HINT family.

RefSeq proteins (1): NP_005331* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001310	Histidine_triad_HIT	Family
IPR011146	HIT-like	Domain
IPR019808	Histidine_triad_CS	Conserved_site
IPR036265	HIT-like_sf	Homologous_superfamily

Pfam: PF01230

Catalyzed reactions (Rhea), 1 shown:

• adenosine 5’-phosphoramidate + H2O = NH4(+) + AMP (RHEA:67916)

UniProt features (49 total): mutagenesis site 17, sequence variant 6, strand 6, modified residue 5, helix 5, binding site 4, initiator methionine 1, chain 1, domain 1, short sequence motif 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

61 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6J64	X-RAY DIFFRACTION	0.95
6J5S	X-RAY DIFFRACTION	1.02
6YQM	X-RAY DIFFRACTION	1.02
5WAA	X-RAY DIFFRACTION	1.1
6N3X	X-RAY DIFFRACTION	1.1
6B42	X-RAY DIFFRACTION	1.13
5WA9	X-RAY DIFFRACTION	1.15
5KM3	X-RAY DIFFRACTION	1.2
5I2F	X-RAY DIFFRACTION	1.25
5KM2	X-RAY DIFFRACTION	1.25
5O8I	X-RAY DIFFRACTION	1.27
5IPC	X-RAY DIFFRACTION	1.3
5KLY	X-RAY DIFFRACTION	1.3
5WA8	X-RAY DIFFRACTION	1.3
6J5Z	X-RAY DIFFRACTION	1.3
9QTC	X-RAY DIFFRACTION	1.3
5ED3	X-RAY DIFFRACTION	1.31
5KMC	X-RAY DIFFRACTION	1.35
3TW2	X-RAY DIFFRACTION	1.38
5KM4	X-RAY DIFFRACTION	1.4
6J65	X-RAY DIFFRACTION	1.42
6G9Z	X-RAY DIFFRACTION	1.43
5IPE	X-RAY DIFFRACTION	1.45
6N3V	X-RAY DIFFRACTION	1.45
1KPF	X-RAY DIFFRACTION	1.5
5EMT	X-RAY DIFFRACTION	1.5
5KLZ	X-RAY DIFFRACTION	1.5
8PA9	X-RAY DIFFRACTION	1.5
4EQE	X-RAY DIFFRACTION	1.52
4EQG	X-RAY DIFFRACTION	1.52

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49773-F1	96.37	0.94

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 112 (tele-amp-histidine intermediate)

Ligand- & substrate-binding residues (4): 43–44; 99; 105–107; 112–114

Post-translational modifications (5): 21, 30, 45, 72, 2

Mutagenesis-validated functional residues (17):

Position	Phenotype
33	loss of sumo-specific isopeptidase activity.
34	reduced sumo-specific isopeptidase activity.
38	no effect on sumo-specific isopeptidase activity.
43	approximately 50-fold increased affinity for tryptamine adenosine phosphoramidate.
44	approximately 10-fold increased affinity for tryptamine adenosine phosphoramidate.
44	approximately 30-fold increased affinity for tryptamine adenosine phosphoramidate.
51	no effect on affinity for 3-indolepropionic acyl-adenylate but a 13.8-fold increased affinity for tryptamine adenosine p
57	loss of sumo-specific isopeptidase activity.
97	loss of dimerization. strongly reduced adenosine 5’-monophosphoramidase activity. a 110-fold increased affinity for 3-in
97	loss of dimerization. strongly reduced adenosine 5’-monophosphoramidase activity. a 128-fold increased affinity for 3-in
97	loss of sumo-specific isopeptidase activity.
105	reduces adenosine 5’-monophosphoramidase activity.
107	reduces adenosine 5’-monophosphoramidase activity.
110	no significant effect on affinity for 3-indolepropionic acyl-adenylate and tryptamine adenosine phosphoramidate monoeste
114	nearly abolishes adenosine 5’-monophosphoramidase activity. a 3-fold increased affinity for 3-indolepropionic acyl-adeny
114	loss of sumo-specific isopeptidase activity.
123	nearly abolishes adenosine 5’-monophosphoramidase activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-9824594	Regulation of MITF-M-dependent genes involved in apoptosis
R-HSA-9825892	Regulation of MITF-M-dependent genes involved in cell cycle and proliferation
R-HSA-9856649	Transcriptional and post-translational regulation of MITF-M expression and activity

MSigDB gene sets: 392 (showing top): GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, TGCGCANK_UNKNOWN, KAAB_FAILED_HEART_ATRIUM_DN, MODULE_151, GCM_NPM1, MORF_UBE2I, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, HSIAO_HOUSEKEEPING_GENES, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_PEPTIDYL_LYSINE_MODIFICATION, GOBP_POSITIVE_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_APOPTOTIC_SIGNALING_PATHWAY

GO Biological Process (8): regulation of DNA-templated transcription (GO:0006355), proteolysis (GO:0006508), signal transduction (GO:0007165), purine ribonucleotide catabolic process (GO:0009154), protein desumoylation (GO:0016926), positive regulation of calcium-mediated signaling (GO:0050850), intrinsic apoptotic signaling pathway by p53 class mediator (GO:0072332), apoptotic process (GO:0006915)

GO Molecular Function (9): nucleotide binding (GO:0000166), protein kinase C binding (GO:0005080), hydrolase activity (GO:0016787), deSUMOylase activity (GO:0016929), adenosine 5’-monophosphoramidase activity (GO:0043530), catalytic activity (GO:0003824), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234)

GO Cellular Component (8): histone deacetylase complex (GO:0000118), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
MITF-M-dependent gene expression	2
MITF-M-regulated melanocyte development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
protein metabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
purine nucleotide catabolic process	1
purine ribonucleotide metabolic process	1
ribonucleotide catabolic process	1
peptidyl-lysine modification	1
protein modification by small protein removal	1
calcium-mediated signaling	1
regulation of calcium-mediated signaling	1
positive regulation of intracellular signal transduction	1
signal transduction by p53 class mediator	1
intrinsic apoptotic signaling pathway	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
protein kinase binding	1
catalytic activity	1
cysteine-type peptidase activity	1
ubiquitin-like protein peptidase activity	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides	1
molecular_function	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
nucleoplasm	1
nuclear protein-containing complex	1
catalytic complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

1921 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HINT1	TRIM29	Q14134	826
HINT1	RGS20	O76081	751
HINT1	CTSA	P10619	744
HINT1	DES	P17661	742
HINT1	FHIT	P49789	734
HINT1	CES1	P23141	714
HINT1	OPRM1	P35372	675
HINT1	RGS17	Q9UGC6	657
HINT1	MAPDA	Q6DHV7	615
HINT1	HINT3	Q9NQE9	612
HINT1	RUVBL2	Q9Y230	583
HINT1	MITF	O75030	582
HINT1	KARS1	Q15046	499
HINT1	GFAP	P14136	490
HINT1	APTX	Q7Z2E3	453

IntAct

75 interactions, top by confidence:

A	B	Type	Score
CDK9	AIP	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
HINT1	CPSF7	psi-mi:“MI:0915”(physical association)	0.560
SNRNP27	UBA6	psi-mi:“MI:0914”(association)	0.530
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
HINT1	HINT1	psi-mi:“MI:0407”(direct interaction)	0.440
GNL1	HINT1	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
ERBB3	HINT1	psi-mi:“MI:0915”(physical association)	0.370
HINT1	CDC16	psi-mi:“MI:0915”(physical association)	0.370
TRIM29	HINT1	psi-mi:“MI:0915”(physical association)	0.370
PHOSPHO1	DDX39A	psi-mi:“MI:0914”(association)	0.350
SOD1	NPEPPSL1	psi-mi:“MI:0914”(association)	0.350
DND1	RPSA2	psi-mi:“MI:0914”(association)	0.350
PRNP	CARNS1	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
ACTL6A	RAP1BL	psi-mi:“MI:0914”(association)	0.350
CDK9	AIP	psi-mi:“MI:0914”(association)	0.350
SNX24	STRN	psi-mi:“MI:0914”(association)	0.350
HDAC7	ZMYM6	psi-mi:“MI:0914”(association)	0.350
JMJD6	EEF1E1	psi-mi:“MI:0914”(association)	0.350
KDM4D	SMCHD1	psi-mi:“MI:0914”(association)	0.350
RPA3	XRCC6	psi-mi:“MI:0914”(association)	0.350

BioGRID (240): HINT1 (Affinity Capture-MS), HINT1 (Affinity Capture-MS), HINT1 (Affinity Capture-MS), HINT1 (Affinity Capture-RNA), AKR1B1 (Co-fractionation), AKR1B10 (Co-fractionation), AKR1B15 (Co-fractionation), DUT (Co-fractionation), ENO1 (Co-fractionation), ENO2 (Co-fractionation), ENO3 (Co-fractionation), FABP3 (Co-fractionation), FABP5 (Co-fractionation), FABP7 (Co-fractionation), FKBP1A (Co-fractionation)

ESM2 similar proteins: A1VYP2, A9A4N5, A9NFI4, B2TS69, B3CME9, B3PM96, C4LYI2, O07513, O07817, O66536, O84390, O94586, P0ACE7, P0ACE8, P0ACE9, P26724, P32083, P32084, P35136, P42855, P42856, P44956, P47378, P49773, P49774, P53795, P57438, P62958, P62959, P64382, P64383, P70349, P73481, P75504, P80912, P94252, P95937, Q0SRS4, Q0TP54, Q23921

Diamond homologs: C4LYI2, O07513, O07817, O66536, O76463, O84390, O94586, P0A5B6, P0ACE7, P0ACE8, P0ACE9, P26724, P32083, P32084, P42855, P42856, P44956, P47378, P49773, P49774, P49776, P53795, P57438, P62958, P62959, P64382, P64383, P70349, P73481, P75504, P80912, P94252, P95937, P9WML2, P9WML3, Q04344, Q1KZG4, Q23921, Q28BZ2, Q58276

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

151 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	7
Uncertain significance	59
Likely benign	36
Benign	16

Top pathogenic / likely-pathogenic (28)

Variant ID	HGVS	Classification
1013268	NM_005340.7(HINT1):c.100G>T (p.Glu34Ter)	Pathogenic
1048596	NM_005340.7(HINT1):c.99del (p.Phe33fs)	Pathogenic
1070519	NM_005340.7(HINT1):c.283C>T (p.Arg95Ter)	Pathogenic
1073842	NC_000005.9:g.(?_130495140)_130500898del	Pathogenic
1073843	NC_000005.9:g.(?130500743)(130501051_?)del	Pathogenic
1333249	NM_005340.7(HINT1):c.292del (p.Val97_Val98insTer)	Pathogenic
1453950	NM_005340.7(HINT1):c.157del (p.Leu53fs)	Pathogenic
2425337	NC_000005.9:g.(?130495140)(130500898_?)del	Pathogenic
2752806	NM_005340.7(HINT1):c.190del (p.Ser64fs)	Pathogenic
37312	NM_005340.7(HINT1):c.110G>C (p.Arg37Pro)	Pathogenic
37313	NM_005340.7(HINT1):c.250T>C (p.Cys84Arg)	Pathogenic
37316	NM_005340.7(HINT1):c.152A>G (p.His51Arg)	Pathogenic
37317	NM_005340.7(HINT1):c.184C>T (p.Gln62Ter)	Pathogenic
543794	NC_000005.10:g.(?131159427)(131165225_?)del	Pathogenic
637252	NM_005340.7(HINT1):c.316C>T (p.Gln106Ter)	Pathogenic
637254	NM_005340.7(HINT1):c.368G>A (p.Trp123Ter)	Pathogenic
645822	NM_005340.7(HINT1):c.2T>C (p.Met1Thr)	Pathogenic
659256	NM_005340.7(HINT1):c.329_330dup (p.Val111fs)	Pathogenic
659597	NC_000005.10:g.(?131159273)(131165358_?)del	Pathogenic
688891	GRCh37/hg19 5q23.3(chr5:130138490-130513653)x1	Pathogenic
870703	NM_005340.7(HINT1):c.151_152del (p.His51fs)	Pathogenic
1524005	NM_005340.7(HINT1):c.111+2del	Likely pathogenic
1676723	NM_005340.7(HINT1):c.278G>T (p.Gly93Val)	Likely pathogenic
1916267	NM_005340.7(HINT1):c.112-1del	Likely pathogenic
3896880	NM_005340.7(HINT1):c.112-2A>G	Likely pathogenic
545660	NM_005340.7(HINT1):c.289G>A (p.Val97Met)	Likely pathogenic
545661	NM_005340.7(HINT1):c.112T>C (p.Cys38Arg)	Likely pathogenic
560367	NM_005340.7(HINT1):c.209A>G (p.Asp70Gly)	Likely pathogenic

SpliceAI

1604 predictions. Top by Δscore:

Variant	Effect	Δscore
5:131159607:AGAAG:A	acceptor_gain	1.0000
5:131159608:GAAG:G	acceptor_gain	1.0000
5:131159608:GAAGC:G	acceptor_loss	1.0000
5:131159610:AG:A	acceptor_gain	1.0000
5:131159611:GCTG:G	acceptor_loss	1.0000
5:131159612:C:CC	acceptor_gain	1.0000
5:131159612:C:T	acceptor_loss	1.0000
5:131159613:T:G	acceptor_loss	1.0000
5:131162566:A:AC	donor_gain	1.0000
5:131162566:ACTT:A	donor_loss	1.0000
5:131162567:C:CC	donor_gain	1.0000
5:131162569:TA:T	donor_loss	1.0000
5:131162570:A:AC	donor_gain	1.0000
5:131162570:AC:A	donor_loss	1.0000
5:131162571:C:CA	donor_gain	1.0000
5:131162571:CA:C	donor_gain	1.0000
5:131162571:CACT:C	donor_gain	1.0000
5:131162571:CACTT:C	donor_gain	1.0000
5:131162672:AGGCA:A	acceptor_gain	1.0000
5:131162673:GGCA:G	acceptor_gain	1.0000
5:131162674:GCA:G	acceptor_gain	1.0000
5:131162675:CA:C	acceptor_gain	1.0000
5:131162675:CAC:C	acceptor_gain	1.0000
5:131162676:AC:A	acceptor_loss	1.0000
5:131162677:C:CC	acceptor_gain	1.0000
5:131180165:AAGG:A	donor_loss	1.0000
5:131180166:AGGT:A	donor_loss	1.0000
5:131180167:GGTA:G	donor_loss	1.0000
5:131180168:G:GG	donor_gain	1.0000
5:131180169:T:G	donor_loss	1.0000

AlphaMissense

830 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:131162624:A:T	I55K	0.997
5:131159544:C:G	R95P	0.995
5:131162669:G:T	A40D	0.995
5:131165149:A:C	F19L	0.995
5:131165149:A:T	F19L	0.995
5:131165151:A:G	F19L	0.995
5:131159484:A:T	V115D	0.994
5:131159574:G:T	A85D	0.994
5:131162666:A:G	F41S	0.994
5:131159461:A:G	W123R	0.993
5:131159461:A:T	W123R	0.993
5:131162624:A:C	I55R	0.993
5:131162635:A:C	H51Q	0.993
5:131162635:A:T	H51Q	0.993
5:131162676:A:G	C38R	0.993
5:131159486:A:C	H114Q	0.992
5:131159486:A:T	H114Q	0.992
5:131159488:G:C	H114D	0.992
5:131159494:G:C	H112D	0.992
5:131159586:C:T	G81D	0.992
5:131162627:A:T	V54E	0.992
5:131162674:G:C	C38W	0.992
5:131159478:C:T	G117E	0.991
5:131159488:G:T	H114N	0.991
5:131162630:A:G	L53P	0.991
5:131159505:A:T	V108D	0.990
5:131162630:A:T	L53Q	0.990
5:131162637:G:C	H51D	0.990
5:131162665:G:C	F41L	0.990
5:131162665:G:T	F41L	0.990

dbSNP variants (sampled 300 via entrez): RS1000008057 (5:131160747 T>A,C), RS1000230091 (5:131163128 C>A), RS1000338572 (5:131163330 C>A,T), RS1000612188 (5:131162028 C>T), RS1000676774 (5:131158994 T>C), RS1001639784 (5:131164525 G>A), RS1002701183 (5:131162038 A>G), RS1002780012 (5:131161688 T>C), RS1002847119 (5:131164537 A>C), RS10036296 (5:131163642 C>A,G,T), RS1003752836 (5:131159446 C>T), RS1004422691 (5:131162307 A>G), RS1004589306 (5:131167185 T>C), RS1004789005 (5:131164499 A>G), RS1005612559 (5:131159937 G>A,T)

Disease associations

OMIM: gene MIM:601314 | disease phenotypes: MIM:137200, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
Gamstorp-Wohlfart syndrome	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease	Definitive	AR

Mondo (3): Gamstorp-Wohlfart syndrome (MONDO:0007646), peripheral neuropathy (MONDO:0005244), Charcot-Marie-Tooth disease (MONDO:0015626)

Orphanet (2): Autosomal recessive axonal neuropathy with neuromyotonia (Orphanet:324442), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166)

HPO phenotypes

57 total (30 of 57 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000975	Hyperhidrosis
HP:0001171	Split hand
HP:0001256	Mild intellectual disability
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001315	Reduced tendon reflexes
HP:0001328	Specific learning disability
HP:0001371	Flexion contracture
HP:0001760	Abnormal foot morphology
HP:0001761	Pes cavus
HP:0001771	Achilles tendon contracture
HP:0002166	Impaired vibration sensation in the lower limbs
HP:0002273	Tetraparesis
HP:0002356	Writer’s cramp
HP:0002359	Frequent falls
HP:0002380	Fasciculations
HP:0002411	Myokymia
HP:0002486	Myotonia
HP:0002505	Loss of ambulation
HP:0002936	Distal sensory impairment
HP:0002943	Thoracic scoliosis
HP:0003202	Skeletal muscle atrophy
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003376	Steppage gait
HP:0003390	Sensory axonal neuropathy
HP:0003394	Muscle spasm
HP:0003401	Paresthesia
HP:0003409	Distal sensory impairment of all modalities
HP:0003438	Absent Achilles reflex

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST004131_32	Inflammatory bowel disease	4.000000e-27
GCST004132_10	Crohn’s disease	6.000000e-36
GCST004133_36	Ulcerative colitis	2.000000e-06
GCST010701_41	Cortical surface area (MOSTest)	1.000000e-20
GCST010702_96	Subcortical volume (MOSTest)	2.000000e-08
GCST010703_160	Brain morphology (MOSTest)	3.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5878 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs3852209	Other	3	nicotine	Smoking Cessation;Tobacco Use Disorder
rs3852209	Efficacy	3	nicotine	Tobacco Use Disorder

PharmGKB variants

6 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3852209	HINT1	3	2.75	2	nicotine
rs2551038	HINT1		0.00	0
rs3864283	HINT1		0.00	0
rs2278060	HINT1		0.00	0
rs7728773	HINT1		0.00	0
rs4696	HINT1		0.00	0

Binding affinities (BindingDB)

5 measured of 5 human assays (5 total across all organisms); most potent 5 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
[(2R,4S,5R)-3,4-dihydroxy-5-imidazo[2,1-f]purin-3-yloxolan-2-yl]methyl N-[3-(1H-indol-3-yl)propanoyl]sulfamate	KD	230 nM	US-10513520: Sulfamide and sulfamate inhibitors of hHint1
[(2R,3R,4S,5R)-5-(2-amino-6-oxo-2,3,4,5-tetrahydro-1H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl N-[3-(1H-indol-3-yl)propanoyl]sulfamate	KD	810 nM	US-10513520: Sulfamide and sulfamate inhibitors of hHint1
N-[[(2R,4S,5R)-5-(2-amino-6-oxo-2,3,4,5-tetrahydro-1H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfamoyl]-3-(1H-indol-3-yl)propanamide	KD	920 nM	US-10513520: Sulfamide and sulfamate inhibitors of hHint1
[(2R,4S,5R)-3,4-dihydroxy-5-(2-imino-6-oxo-5H-purin-9-yl)oxolan-2-yl]methyl N-butanoylsulfamate	KD	2900 nM	US-10513520: Sulfamide and sulfamate inhibitors of hHint1
[(2R,4S,5R)-3,4-dihydroxy-5-(2-imino-6-oxo-5H-purin-9-yl)oxolan-2-yl]methyl N-[2-(1H-indol-3-yl)ethyl]carbamate	KD	3650 nM	US-10513520: Sulfamide and sulfamate inhibitors of hHint1

ChEMBL bioactivities

27 potent at pChembl≥5 of 33 total, top 26 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.26	Kd	5.514	nM	CHEMBL3752910
8.26	ED50	5.514	nM	CHEMBL3752910
6.64	Kd	230	nM	CHEMBL4471567
6.64	Kd	230	nM	CHEMBL4587255
6.64	Kd	230	nM	CHEMBL5884587
6.50	Kd	320	nM	CHEMBL3140272
6.50	Kd	317.8	nM	CHEMBL5653589
6.50	ED50	317.8	nM	CHEMBL5653589
6.09	Kd	810	nM	CHEMBL4455776
6.09	Kd	810	nM	CHEMBL4537959
6.09	Kd	810	nM	CHEMBL5912036
6.04	Kd	920	nM	CHEMBL4549820
6.04	Kd	920	nM	CHEMBL4547823
6.04	Kd	920	nM	CHEMBL5834786
6.00	IC50	1000	nM	CHEMBL3140272
6.00	Kd	1010	nM	CHEMBL4549100
6.00	IC50	1000	nM	CHEMBL1934757
5.61	Kd	2450	nM	CHEMBL4527477
5.54	Kd	2900	nM	CHEMBL4468179
5.54	Kd	2900	nM	CHEMBL4532499
5.54	Kd	2900	nM	CHEMBL5821808
5.46	Kd	3430	nM	CHEMBL4524307
5.44	Kd	3650	nM	CHEMBL1934757
5.44	Kd	3650	nM	CHEMBL5871562
5.28	Kd	5200	nM	CHEMBL4543014
5.09	Kd	8090	nM	CHEMBL4572000

PubChem BioAssay actives

9 with measured affinity, of 78 total; 8 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148504: Binding affinity to human HINT1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0055	uM
N,N-diethylethanamine;[(2R,3S,4R,5R)-3,4-dihydroxy-5-imidazo[2,1-f]purin-3-yloxolan-2-yl]methyl N-[3-(1H-indol-3-yl)propanoyl]sulfamate	1632741: Binding affinity to His-tagged human full length HINT1 expressed in Rosetta2 pLysS cells by isothermal titration calorimetric assay	kd	0.2300	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148504: Binding affinity to human HINT1 incubated for 45 mins by Kinobead based pull down assay	kd	0.3178	uM
5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-N-[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfamoyl]pentanamide	1632741: Binding affinity to His-tagged human full length HINT1 expressed in Rosetta2 pLysS cells by isothermal titration calorimetric assay	kd	0.3200	uM
[(2R,3S,4R,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl N-[3-(1H-indol-3-yl)propanoyl]sulfamate;N,N-diethylethanamine	1632741: Binding affinity to His-tagged human full length HINT1 expressed in Rosetta2 pLysS cells by isothermal titration calorimetric assay	kd	0.8100	uM
N-[[(2R,3S,4R,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methylsulfamoyl]-3-(1H-indol-3-yl)propanamide;N,N-diethylethanamine	1632741: Binding affinity to His-tagged human full length HINT1 expressed in Rosetta2 pLysS cells by isothermal titration calorimetric assay	kd	0.9200	uM
[(2R,3S,4R,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl N-butanoylsulfamate;N,N-diethylethanamine	1632741: Binding affinity to His-tagged human full length HINT1 expressed in Rosetta2 pLysS cells by isothermal titration calorimetric assay	kd	2.9000	uM
[(2R,3S,4R,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl N-[2-(1H-indol-3-yl)ethyl]carbamate	1632742: Binding affinity to recombinant human HINT1 by isothermal titration calorimetric assay	kd	3.6500	uM

CTD chemical–gene interactions

50 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	3
Particulate Matter	decreases expression, increases abundance, increases expression	3
bisphenol A	affects expression, increases expression	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Fluorouracil	increases expression	2
Hydrogen Peroxide	decreases expression, affects cotreatment, increases expression	2
Smoke	decreases expression	2
Cadmium Chloride	increases abundance, increases expression	2
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
arsenite	affects binding, increases reaction	1
perfluorooctanoic acid	increases expression	1
sulindac sulfone	increases expression	1
4-hydroxy-2-nonenal	decreases expression	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	decreases expression	1
tanespimycin	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	increases expression	1
dibutyldi(4-chlorobenzohydroxamato)tin(IV)	increases expression	1
VER 155008	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenates	affects cotreatment, increases expression	1
Arsenic	increases abundance, increases expression	1
Atrazine	affects cotreatment, increases expression	1

ChEMBL screening assays

32 unique, capped per target: 17 admet, 15 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1040084	Binding	Ratio of kcat to km for human HINT1	Identification of the amino acid-AZT-phosphoramidase by affinity T7 phage display selection. — Bioorg Med Chem Lett
CHEMBL3240103	ADMET	Drug metabolism in human K562 cell lysate assessed as HINT-1-mediated compound formation by measuring retention time at 1 mM after 22 hrs by RP-HPLC analysis relative to control	N-Acyl-phosphoramidates as potential novel form of gemcitabine prodrugs. — Bioorg Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1TN	Abcam HeLa HINT1 KO	Cancer cell line	Female
CVCL_E1Z3	HAP1 HINT1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00380965	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Chemotherapy-Induced Neuropathy
NCT00487981	PHASE4	TERMINATED	Spinal Cord Stimulation for Painful Diabetic Neuropathy
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT01192113	PHASE4	COMPLETED	Safety and Efficacy of Mecobalamin Injection in Peripheral Neuropathies Patients (Study JGAZSY091109)
NCT01373983	PHASE4	COMPLETED	Intrathecal Bolus Doses of Ziconotide
NCT01458015	PHASE4	TERMINATED	Tapentadol Versus Oxycodone - a Mechanism-based Treatment Approach in Neuropathic Pain
NCT02074267	PHASE4	COMPLETED	Clinical Study for Assessment of the Efficacy of Gabapentin (Carbatin and Neurontin) in Patients With Neuropathy Pain
NCT02372149	PHASE4	UNKNOWN	IVIg for Demyelination in Diabetes Mellitus
NCT02670161	PHASE4	ENROLLING_BY_INVITATION	Quality Improvement and Practice Based Research in Neurology Using the EMR
NCT07022938	PHASE4	COMPLETED	Nutritional Supplement for Treating Chemotherapy Induced Neuropathy
NCT07025005	PHASE4	RECRUITING	Fenofibrate Role in the Prophylaxis From Peripheral Neuropathy Induced by Bortezomib, Lenalidomide and Dexamethasone (VRd) Protocol in the Treatment of Patients With Multiple Myeloma (MM)
NCT00058071	PHASE3	COMPLETED	Amifostine in Treating Peripheral Neuropathy in Patients Who Have Received Chemotherapy for Cancer
NCT00125268	PHASE3	TERMINATED	Near Infrared Light for the Treatment of Painful Peripheral Neuropathy
NCT00195013	PHASE3	COMPLETED	Randomized Placebo-Controlled Trial of Glutamine for Breast Cancer Patients With Peripheral Neuropathy
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